The present invention is concerned with 3-(amino- or aminoalkyl) pyridinone derivatives which inhibit the reverse transcriptase of the Human Immunodeficiency Virus (HIV).
It relates moreover to the use of such compounds for treating HIV-related diseases.
Furthermore it relates to a process for the preparation of these compounds.
It is known that some pyrimidinone and pyridinone derivatives inhibit HIV reverse transcriptase.
In particular, derivatives from 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) are well known for their HIV1 reverse transcriptase inhibitory properties.
European Patent Application EP-0 462 800 (Merck and Company Inc.) discloses pyridinones being substituted on position 3 with an aryl or heterocyclic group, linked to the pyridinone ring through a chain.
Unfortunately, strains resistant to these compounds appeared Thus, their use in therapeutical treatments is questionable.
4-aryl-thio-pyridinones have been more recently disclosed by DOLLE et al. (1995, J. Med. Chem., 38, 4679-4686), and in the corresponding PCT Patent Application WO 97/05 113.
However, their activities are still moderate and their use in human therapy also could lead to the emergence of resistant strains.
The most active thio pyridinones disclosed therein have a 50% inhibitory concentration of virus multiplication (IC50) for nevirapine resistant strains of about 260 nM.
The inventors have found a new pyridinone derivative family which show better HIV inhibitory properties.
They have moreover found a new process for obtaining these compounds.
The present invention relates to compounds having the following general formula I. 
wherein
Q represents xe2x80x94NR1R2 or xe2x80x94R0NR1R2 wherein:
R0 represents C1-6 alkanediyl;
R1 and R2 each independently represent C1-6alkyl or C3-6alkenyl; said C1-6alkyl and C3-6alkenyl may be substituted with one, two or three substituents selected from hydroxy, C1-4alkyloxy, C1-4alkylthio, aryloxy, arylthio, amino, mono- or di(C1-4alkyl)amino and aryl; or
R1 and R2 taken together may form a bivalent radical xe2x80x94R1-R2xe2x80x94 wherein xe2x80x94R1-R2xe2x80x94 represents xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94NR7xe2x80x94(CH2)2, xe2x80x94(CH2)2xe2x80x94CH(NHR7)xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)n, wherein R7 represents hydrogen or C1-4alkyl and n represents 2, 3, 4, 5 or 6;
R3 represents aryl or a monocyclic or bicyclic heterocycle selected from pyridinyl, pyrimidinyl, thiazolinyl, furanyl, thienyl, imidazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl; said monocyclic or bicyclic heterocycle may optionally be substituted with one, two or three substituents each independently selected from hydroxy, C1-4-alkyl, C1-4alkoxy, halo, trifluoromethyl, dimethylenoxy or phenyl,
R4 and R5 each independently represent hydrogen, C1-6alkyl, C3-6alkenyl, C1-4alkoxy, C1-4alkyloxy, C1-4alkyl, amino, mono- or di(C1-4alkyl) amino, formyl, C1-4alkylcarbonyl, carboxyl, C1-4 alkyloxycarbonyl, or C1-4alkylaminocarbonyl; wherein C1-6alkyl and C3-6alkenyl may be substituted with one, two or three substituents selected from hydroxy, C1-4alkyloxy, C1-4alkyl thio, aryloxy, arylthio, amino, mono- or di(C1-4alkyl)amino and aryl; or
R4 and R5 taken together form a bivalent radical of formula xe2x80x94R4-R5xe2x80x94 wherein xe2x80x94R4-R5xe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)txe2x80x94, wherein t represents 3 or 4;
R6 represents hydrogen, hydroxy, C1-4alkyloxy, C1-6alkyl, C3-6alkenyl, aryl, C1-4alkyl, amino, mono- or di(C1-4alkyl)amino or alkylaryl;
Y represents O or S;
X represents a radical of formula:
xe2x80x94(CH2)pxe2x80x94
xe2x80x94(CH2)qxe2x80x94Zxe2x80x94(CH2)rxe2x80x94
or
xe2x80x94COxe2x80x94
wherein p represents 1, 2, 3, 4 or 5;
q represents 0, 1, 2, 3, 4 or 5;
r represents 0, 1, 2 or 3;
Z represents NR8, C(xe2x95x90O), CHOH, CHNR8R9; CF2, O, S or CHxe2x95x90CH; wherein R8 and R9 each independently represent hydrogen or C1-4 alkyl;
or N-oxides, stereochemically isomeric forms or a pharmaceutically acceptable addition salts thereof.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C1-4-alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof containing 5 to 6 carbon atoms such as, for example, pentyl, hexyl or the like; C3-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of said C3-6alkenyl being connected to a nitrogen atom preferably is saturated; C1-6-alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. The term  less than  less than C(xe2x95x90O) greater than  greater than  refers to a carbonyl group. Aryl is phenyl or phenyl substituted with one, two or three substituents selected from C1-4alkyl, C1-4alkyloxy, halo and trifluoromethyl,
Preferred compounds according to the present invention are those in which X represents xe2x80x94CH2xe2x80x94 or C (xe2x95x90O) and R3 represents a phenyl group, substituted with two methyl groups, and the most preferred of them are those wherein R3 represents a phenyl group substituted, in each meta position, with two methyl groups.
Preferably, in the compounds according to the present invention, R1 and R2 represent each a methyl group, R4 represents an ethyl group, R5 represents a methyl group and/or R6 represents a hydrogen atom.
The most preferred compound of this invention is the 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.
The compounds in which X is xe2x80x94CH2xe2x80x94, R3 represents a phenyl group optionally substituted, Y represents O and R6 represents a hydrogen atom can be obtained by the general process represented on FIG. 1.
This first process comprises the following steps:
a) reacting a pyridine (2), substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C1-C6 alkyllithium, resulting in a lithiated derivate (3) of the said pyridine.
b) transforming the lithiated derivate (3) into an organocopper reagent by reacting it with a complex formed by Cu I and dimethyl sulphide.
c) obtaining the pyridinone (4) by reacting the organocopper reagent with optionally substituted benzyl halide.
d) hydrolysing the protected pyridinone (4) and obtaining the deprotected pyridinone (5).
e) substituting the 3-amine group of the pyridinone (5) and obtaining the pyridinone (6).
This first process is summarized in the reaction Scheme I hereinafter: 
In this process R10 and R11 represent independently C1-C6 alkyl. In a preferred embodiment, R10 is a methyl group and R11 is a tert-butyl group.
The C1-C6 alkyllithium, reacted with the pyridine(2) can be a n-butyllithium.
The optionally substituted benzyl halide used in the step c) is preferably benzyl bromide.
The hydrolysis of the protected pyridinone(4), resulting in its deprotection, is advantageously obtained by adding hydrochloric acid to the pyridinone(4) and refluxing the mixture.
In a preferred embodiment, the amino group in position 3 of the pyridinone ring, deprotected during the step (d) is substituted by alkylation, by the Eschweiler-Clarke reaction.
Compounds wherein X represents xe2x80x94(CH2)qxe2x80x94Zxe2x80x94(CH2)rxe2x80x94, Y represents O, R3 is an optionally substituted phenyl group and R6 is an hydrogen atom can be obtained by a similar process.
Compounds wherein X represents C (xe2x95x90O), or xe2x80x94CH2xe2x80x94, Y represents O, R3 is an optionally substituted phenyl group and R6 is an hydrogen atom can be obtained by a second process.
In this second process, the lithiated derivative (3) is reacted with an optionally substituted benzaldehyde, resulting in the intermediates of formula (7).
The intermediate (7) is oxidized to intermediate (8).
The intermediate (8) is thereafter deprotected by hydrolysis, as in the first process, resulting in the pyridinone (9) of general formula I.
This second process is summarized in the reaction scheme II hereinafter. 
Preferably the oxidation of the intermediate (7) is performed in the presence of manganese dioxide.
The intermediate (7) can also be transformed into corresponding ester (10) wherein R12 represents a C1-C4 alkyl group whose hydrogenolysis provides pyridinone(4) in better yields. Preferably, the ester (10) wherein R12 is CH3 is prepared by treatment of intermediate (7) with acetic anhydride. Subsequently hydrogenolysis is performed under hydrogen atmosphere and in the presence of a catalyst, especially 30% paladized charcoal. This process is summarized in the reaction scheme III 
Other compounds of general formula I, and wherein X is (CH2)p or (CH2)qxe2x80x94Zxe2x80x94(CH2)r or C(xe2x95x90O), and R3 is other than phenyl and R6 is other than hydrogen can be obtained by these processes, appropriately adapted by the man skilled in the art.
The compounds according to the present invention, in which X is S can be obtained by the process described in the article of DOLLE et al. (1995, previously cited) or in the corresponding patent application WO 97/05 113, the contents of which are included in the present application.
The compounds can also be obtained by other processes known by the man skilled in the art.
The present invention relates moreover to the intermediates of the processes hereabove disclosed. In particular it relates to the lithiated derivative of formula (3).
The compounds of the present invention are useful in the inhibition of HIV reverse transcriptase, and in particular HIV-1 reverse transcriptase and the prevention or treatment of infection by the human immuno deficiency virus (HIV) and of HIV-related diseases, such as AIDS.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including sub-cutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tectoniques), by inhalation spray, or rectally, in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
Thus, another object of the present invention is a method, and a pharmaceutical composition for treating HIV related diseases, HIV infection, and in particular AIDS.
The invention relates also to these compounds for use as medecine and to their use for the manufacture of a medecine for the treatment of HIV related diseases, HIV infection, and in particular AIDS.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectable preparations, or suppositories.